tbuckley/cabot-search huggingface dataset:
Repurposing small molecules for nephronophthisis and related renal ciliopathies
Authors: Alexandre Benmerah, Luis Briseño-Roa, Jean-Philippe Annereau, Sophie Saunier
Journal: Kidney International (2023)

Nephronophthisis is an autosomal recessive tubulointerstitial nephropathy, belonging to the ciliopathy disorders, characterized by fibrosis and/or cysts. It is the most common genetic cause of kidney failure in children and young adults. Clinically and genetically heterogeneous, it is caused by variants in ciliary genes, resulting in either an isolated kidney disease or syndromic forms in association with other manifestations of ciliopathy disorders. No curative treatment is currently available. Over the past 2 decades, advances in understanding disease mechanisms have identified several dysregulated signaling pathways, some shared with other cystic kidney diseases. Notably, molecules previously developed to target these pathways have shown promising beneficial effects in orthologous mouse models. In addition to these knowledge-based repurposing approaches, unbiased "in cellulo" phenotypic screens of "repurposing" libraries identified small molecules able to rescue the ciliogenesis defects observed in nephronophthisis conditions. Those compounds appeared to act on relevant pathways and, when tested, showed beneficial nephronophthisis-associated kidney and/or extrarenal defects in mice. In this review, we have summarized those studies that highlight the drug repurposing strategies in the context of a rare disorders, such as nephronophthisis-related ciliopathies, with broad genetic heterogeneity and systemic manifestations but with shared disease mechanisms.
Commentary
Authors: Leon M. G. Moons
Journal: Endoscopy (2023)

Endoscopic full-thickness resection (EFTR) is increasingly used for local resection of suspected T1 colorectal carcinoma (CRC), completing scar excision after an R1/Rx resection of pT1 CRC, and for nonlifting residual or recurrent adenoma. The technique has some important advantages such as an en bloc resection for optimal histological evaluation, the high chance of obtaining an R0 resection especially at the vertical margin, and the technical ability to remove complex polyps by endoscopy, where more conventional techniques would likely fail. Recent publications including large cohorts have shown that the EFTR technique is both safe and effective in a large number of selected and deemed suitable cases.
Baricitinib Improves Bone Properties and Biomechanics in Patients With Rheumatoid Arthritis: Results of the Prospective Interventional <scp>BARE BONE</scp> Trial
Authors: David Simon, Ioanna Minopoulou, Stephan Kemenes, Sara Bayat, Koray Tascilar, Melek Yalcin Mutlu, Larissa Valor‐Méndez, Gerhard Krönke, Axel J. Hueber, Georg Schett, Arnd Kleyer
Journal: Arthritis & Rheumatology (2023)

Rheumatoid arthritis (RA) is characterized by erosive joint damage, deterioration of bone mass, and biomechanics. Preclinical evidence suggests a beneficial effect of Janus kinase inhibition (JAKi) on bone properties, but clinical data are scarce to date. In this study, we evaluated the effect of JAKi through baricitinib (BARI) on 1) volumetric bone mineral density (vBMD), bone microstructure, biomechanics, and erosion repair and 2) synovial inflammation in RA patients.Prospective, single-arm, interventional, open-label, single-center phase 4 study in RA patients with pathological bone status and clinical indication of JAKi (BARE BONE trial). Participants received BARI (4 mg/day) over 52 weeks. To assess bone properties and synovial inflammation, high-resolution computed tomography scans and magnetic resonance imaging were performed at baseline (BL), week 24, and week 52. Clinical response and safety were monitored.Thirty RA patients were included. BARI significantly improved disease activity (Disease Activity Score in 28 joints using the erythrocyte sedimentation rate: 4.82 ± 0.90 to 2.71 ± 0.83) and synovial inflammation (RAMRIS synovitis score: 5.3 [4.2] to 2.7 [3.5]). We observed a significant improvement in trabecular vBMD with a mean change of 6.11 mgHA/mm3 (95% confidence interval [95% CI] 0.01-12.26). Biomechanical properties also improved with mean change from baseline in estimated stiffness of 2.28 kN/mm (95% CI 0.30-4.25) and estimated failure load of 98.8 N (95% CI 15.9-181.7). The number and size of erosions in the metacarpal joints remained stable. No new safety signals with BARI treatment were observed.Bones of RA patients improve with BARI therapy, as shown by an increase in trabecular bone mass and an improvement of biomechanical properties.
Reply to Mattias Höglund’s Letter to the Editor re: Alexander Cox, Niklas Klümper, Johannes Stein, et al. Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2023.03.020
Authors: Niklas Klümper, Alexander Cox, Markus Eckstein
Journal: European Urology (2023)
Shared and Distinctive Transcriptomic and Proteomic Pathways in Adult and Juvenile Dermatomyositis
Authors: James M. Ward, Mythri Ambatipudi, Terrance P. O'Hanlon, Michael A. Smith, Melissa de Los Reyes, Adam Schiffenbauer, Saifur Rahman, Kamelia Zerrouki, Frederick W. Miller, Miguel A. Sanjuan, Jian‐Liang Li, Kerry A. Casey, Lisa G. Rider
Journal: Arthritis & Rheumatology (2023)

Transcript and protein expression were interrogated to examine gene locus and pathway regulation in the peripheral blood of active adult dermatomyositis (DM) and juvenile DM patients receiving immunosuppressive therapies.Expression data from 14 DM and 12 juvenile DM patients were compared to matched healthy controls. Regulatory effects at the transcript and protein level were analyzed by multi-enrichment analysis for assessment of affected pathways within DM and juvenile DM.Expression of 1,124 gene loci were significantly altered at the transcript or protein levels across DM or juvenile DM, with 70 genes shared. A subset of interferon-stimulated genes was elevated, including CXCL10, ISG15, OAS1, CLEC4A, and STAT1. Innate immune markers specific to neutrophil granules and neutrophil extracellular traps were up-regulated in both DM and juvenile DM, including BPI, CTSG, ELANE, LTF, MPO, and MMP8. Pathway analysis revealed up-regulation of PI3K/AKT, ERK, and p38 MAPK signaling, whose central components were broadly up-regulated in DM, while peripheral upstream and downstream components were differentially regulated in both DM and juvenile DM. Up-regulated components shared by DM and juvenile DM included cytokine:receptor pairs LGALS9:HAVCR2, LTF/NAMPT/S100A8/HSPA1A:TLR4, CSF2:CSF2RA, EPO:EPOR, FGF2/FGF8:FGFR, several Bcl-2 components, and numerous glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling.The combination of proteomics and transcript expression by multi-enrichment analysis broadened the identification of up- and down-regulated pathways among active DM and juvenile DM patients. These pathways, particularly those which feed into PI3K/AKT and MAPK signaling and neutrophil degranulation, may be potential therapeutic targets.
Can MSH3 lowering stop HTT repeat expansion in its CAG tract?
Authors: Ross Ferguson, Sarah J. Tabrizi
Journal: Molecular Therapy (2023)

Huntington's disease (HD) is a neurodegenerative repeat expansion disorder caused by an expansion of the CAG trinucleotide repeat present in exon 1 of the huntingtin (HTT) gene. The expanded repeat exhibits instability in somatic tissues, resulting in an inexorable increase in length over the HD gene carrier's lifetime. Although the length of the expanded CAG repeat is the strongest predictor of age at onset and progression, potential genetic modifiers have also been identified. 1 Moss D.J.H. Pardiñas A.F. Langbehn D. Lo K. Leavitt B.R. Roos R. Durr A. Mead S. TRACK-HD investigators REGISTRY investigators et al. Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study. Lancet Neurol. 2017; 16: 701-711 Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar ,2 Genetic Modifiers of Huntington's Disease GeM-HD Consortium Lee J.-M. Correia K. Loupe J. Kim K.-H. Barker D. Hong E.P. Chao M.J. Long J.D. Lucente D. et al. CAG repeat not polyglutamine length determines timing of huntington's disease onset. Cell. 2019; 178: 887-900.e14 Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Many of these modifiers are within DNA repair genes and have been implicated in repeat expansion, including the mismatch repair protein MSH3. The process of somatic repeat expansion in the brain appears to be a major factor in driving disease progression, leading to production of more toxic HTT protein species. As a monogenic disease, many genetic therapeutic approaches past and present aim to ameliorate the effects of the mutant HTT protein by lowering its levels. In this issue of Molecular Therapy, O'Reilly and colleagues 3 O'Reilly D. Belgrad J. Ferguson C. Summers A. Sapp E. McHugh C. Mathews E. Boudi A. Buchwald J. Ly S. et al. Di-valent siRNA mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington's disease. Mol. Ther. 2023; https://doi.org/10.1016/j.ymthe.2023.05.006 Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar demonstrate the potential of an alternative therapeutic intervention to slow the expansion of the CAG repeat by targeting MSH3. They achieve suppression of somatic expansion in two different but complementary HD mouse models by instead lowering the expression of MSH3, using a nucleic acid therapeutic modality established previously by the Khvorova group, the di-valent siRNA (di-siRNA). 4 Alterman J.F. Godinho B.M.D.C. Hassler M.R. Ferguson C.M. Echeverria D. Sapp E. Haraszti R.A. Coles A.H. Conroy F. Miller R. et al. A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat. Biotechnol. 2019; 37: 884-894 Crossref PubMed Scopus (101) Google Scholar
Expert Perspective: Challenges in Sjögren's Disease
Authors: Gaetane Nocturne, Xavier Mariette
Journal: Arthritis & Rheumatology (2023)

The management of Sjögren's disease is challenging because of several factors. Indeed, the clinical presentations are heterogeneous, and one must be able to identify prognostic markers to adapt the follow-up. In addition, there is no validated treatment. Nevertheless, international experts have been working for several years to establish recommendations to guide management. Since research in this field is extremely active, we anticipate the development of effective treatments for our patients in the near future.
Tazemetostat for tumors harboring SMARCB1/SMARCA4 or EZH2 alterations: results from NCI-COG pediatric MATCH APEC1621C
Authors: Susan N Chi, Joanna S Yi, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent D Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Nilsa C Ramirez, Alok Jaju, Joyce C Mhlanga, Elizabeth Fox, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D Williams Parsons
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice assigns patients aged 1-21 years with refractory solid tumors, brain tumors, lymphomas, and histiocytic disorders to phase II trials of molecularly targeted therapies based on detection of predefined genetic alterations. Patients whose tumors harbored EZH2 mutations or loss of SMARCB1 or SMARCA4 by immunohistochemistry were treated with EZH2 inhibitor tazemetostat. Methods Patients received tazemetostat for 28-day cycles until disease progression or intolerable toxicity (max 26 cycles). The primary endpoint was objective response rate; secondary endpoints included progression-free survival and tolerability of tazemetostat. Results Twenty patients (median age = 5 years) enrolled, all evaluable for response and toxicities. The most frequent diagnoses were atypical teratoid rhabdoid tumor (n = 8) and malignant rhabdoid tumor (n = 4). Actionable alterations consisted of SMARCB1 loss (n = 16), EZH2 mutation (n = 3), and SMARCA4 loss (n = 1). One objective response was observed in a patient with non-Langerhans cell histiocytosis with SMARCA4 loss (26 cycles, 1200 mg/m2/dose twice daily). Four patients with SMARCB1 loss had a best response of stable disease: epithelioid sarcoma (n = 2), atypical teratoid rhabdoid tumor (n = 1), and renal medullary carcinoma (n = 1). Six-month progression-free survival was 35% (95% confidence interval [CI] = 15.7% to 55.2%) and 6-month overall survival was 45% (95% CI = 23.1% to 64.7%). Treatment-related adverse events were consistent with prior tazemetostat reports. Conclusions Although tazemetostat did not meet its primary efficacy endpoint in this population of refractory pediatric tumors (objective response rate = 5%, 90% CI = 1% to 20%), 25% of patients with multiple histologic diagnoses experienced prolonged stable disease of 6 months and over (range = 9-26 cycles), suggesting a potential effect of tazemetostat on disease stabilization.
Corrigendum to “Comparison of outward transmission potential between vaccinated and partially vaccinated or unvaccinated individuals with the SARS-CoV-2 delta variant infection” [J Infect 85 (2022) e69–e71]
Authors: Sung Woon Kang, Ji Yeun Kim, Heedo Park, So Yun Lim, Jeonghun Kim, Seongman Bae, Jiwon Jung, Min Jae Kim, Yong Pil Chong, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Man-Seong Park, Sung-Han Kim
Journal: Journal of Infection (2023)
Smoking status and the association between patient-level factors and survival among lung cancer patients
Authors: Nikki M Carroll, Andrea N Burnett-Hartman, Katharine A Rendle, Christine M Neslund-Dudas, Robert T Greenlee, Stacey A Honda, Anil Vachani, Debra P Ritzwoller
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Declines in the prevalence of cigarette smoking, advances in targeted therapies, and implementation of lung cancer screening have changed the clinical landscape for lung cancer. The proportion of lung cancer deaths is increasing in those who have never smoked cigarettes. To better understand contemporary patterns in survival among patients with lung cancer, a comprehensive evaluation of factors associated with survival, including differential associations by smoking status, is needed. Methods Patients diagnosed with lung cancer between January 1, 2010, and September 30, 2019, were identified. We estimated all-cause and lung cancer-specific median, 5-year, and multivariable restricted mean survival time (RMST) to identify demographic, socioeconomic, and clinical factors associated with survival, overall and stratified by smoking status (never, former, and current). Results Analyses included 6813 patients with lung cancer: 13.9% never smoked, 54.2% formerly smoked, and 31.9% currently smoked. All-cause RMST through 5 years for those who never, formerly, and currently smoked was 32.1, 25.9, and 23.3 months, respectively. Lung cancer–specific RMST was 36.3 months, 30.3 months, and 26.0 months, respectively. Across most models, female sex, younger age, higher socioeconomic measures, first-course surgery, histology, and body mass index were positively associated, and higher stage was inversely associated with survival. Relative to White patients, Black patients had increased survival among those who formerly smoked. Conclusions We identify actionable factors associated with survival between those who never, formerly, and currently smoked cigarettes. These findings illuminate opportunities to address underlying mechanisms driving lung cancer progression, including use of first-course treatment, and enhanced implementation of tailored smoking cessation interventions for individuals diagnosed with cancer.
A Laser‐Driven Microrobot for Thermal Stimulation of Single Cells
Authors: Philipp Harder, Nergishan İyisan, Chen Wang, Fabian Kohler, Irina Neb, Harald Lahm, Martina Dreßen, Markus Krane, Hendrik Dietz, Berna Özkale
Journal: Advanced Healthcare Materials (2023)

Here, the study presents a thermally activated cell-signal imaging (TACSI) microrobot, capable of photothermal actuation, sensing, and light-driven locomotion. The plasmonic soft microrobot is specifically designed for thermal stimulation of mammalian cells to investigate cell behavior under heat active conditions. Due to the integrated thermosensitive fluorescence probe, Rhodamine B, the system allows dynamic measurement of induced temperature changes. TACSI microrobots show excellent biocompatibility over 72 h in vitro, and they are capable of thermally activating single cells to cell clusters. Locomotion in a 3D workspace is achieved by relying on thermophoretic convection, and the microrobot speed is controlled within a range of 5-65 µm s-1 . In addition, light-driven actuation enables spatiotemporal control of the microrobot temperature up to a maximum of 60 °C. Using TACSI microrobots, this study targets single cells within a large population, and demonstrates thermal cell stimulation using calcium signaling as a biological output. Initial studies with human embryonic kidney 293 cells indicate a dose dependent change in intracellular calcium content within the photothermally controlled temperature range of 37-57 °C.
ACC/AHA/ASE/ASNC/ASPC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2023 Multimodality Appropriate Use Criteria for the Detection and Risk Assessment of Chronic Coronary Disease
Authors: David E. Winchester, David J. Maron, Ron Blankstein, Ian C. Chang, Ajay J. Kirtane, Raymond Y. Kwong, Patricia A. Pellikka, Jordan M. Prutkin, Raymond Russell, Alexander T. Sandhu
Journal: Journal of the American College of Cardiology (2023)
Inflammasomes and Atherosclerosis: a Mixed Picture
Authors: Alan R. Tall, Karin E. Bornfeldt
Journal: Circulation Research (2023)

The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Moreover, studies in mouse models indicate a causal role of inflammasomes and IL-1β in atherosclerosis. However, recent studies have led to a more granular view of the role of inflammasomes in atherosclerosis. Studies in hyperlipidemic mouse models suggest that prominent activation of the NLRP3 inflammasome requires a second hit such as defective cholesterol efflux, defective DNA repair, clonal hematopoiesis or diabetes. Similarly in humans some mutations promoting clonal hematopoiesis increase coronary artery disease risk in part by promoting inflammasome activation. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2) inflammasome in promoting cardiovascular disease including in some forms of clonal hematopoiesis and diabetes. These developments suggest a precision medicine approach in which treatments targeting inflammasomes or IL-1β might be best employed in clinical settings involving increased inflammasome activation.
Randomized Trial to Assess the Clinical Utility of Renal Allograft Monitoring by Urine CXCL10 Chemokine
Authors: Patricia Hirt-Minkowski, Joelle Handschin, Susanne Stampf, Helmut Hopfer, Thomas Menter, Lisa Senn, Gideon Hönger, Caroline Wehmeier, Patrizia Amico, Jürg Steiger, Michael Koller, Michael Dickenmann, Stefan Schaub
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement This study is the first randomized controlled trial to investigate the clinical utility of a noninvasive monitoring biomarker in renal transplantation. Although urine CXCL10 monitoring could not demonstrate a beneficial effect on 1-year outcomes, the study is a rich source for future design of trials aiming to explore the clinical utility of noninvasive biomarkers. In addition, the study supports the use of urine CXCL10 to assess the inflammatory status of the renal allograft. Background Urine CXCL10 is a promising noninvasive biomarker for detection of renal allograft rejection. The aim of this study was to investigate the clinical utility of renal allograft monitoring by urine CXCL10 in a randomized trial. Methods We stratified 241 patients, 120 into an intervention and 121 into a control arm. In both arms, urine CXCL10 levels were monitored at three specific time points (1, 3, and 6 months post-transplant). In the intervention arm, elevated values triggered performance of an allograft biopsy with therapeutic adaptations according to the result. In the control arm, urine CXCL10 was measured, but the results concealed. The primary outcome was a combined end point at 1-year post-transplant (death-censored graft loss, clinical rejection between month 1 and 1-year, acute rejection in 1-year surveillance biopsy, chronic active T-cell–mediated rejection in 1-year surveillance biopsy, development of de novo donor-specific HLA antibodies, or eGFR &lt;25 ml/min). Results The incidence of the primary outcome was not different between the intervention and the control arm (51% versus 49%; relative risk (RR), 1.04 [95% confidence interval, 0.81 to 1.34]; P = 0.80). When including 175 of 241 (73%) patients in a per-protocol analysis, the incidence of the primary outcome was also not different (55% versus 49%; RR, 1.11 [95% confidence interval, 0.84 to 1.47]; P = 0.54). The incidence of the individual end points was not different as well. Conclusions This study could not demonstrate a beneficial effect of urine CXCL10 monitoring on 1-year outcomes (ClinicalTrials.gov_NCT03140514).
HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy
Authors: MacRae F. Linton, Patricia G. Yancey, Huan Tao, Sean S. Davies
Journal: Circulation Research (2023)

Epidemiologic studies detected an inverse relationship between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major risk factor for ASCVD and suggesting atheroprotective functions of HDL. However, the role of HDL-C as a mediator of risk for ASCVD has been called into question by the failure of HDL-C-raising drugs to reduce cardiovascular events in clinical trials. Progress in understanding the heterogeneous nature of HDL particles in terms of their protein, lipid, and small RNA composition has contributed to the realization that HDL-C levels do not necessarily reflect HDL function. The most examined atheroprotective function of HDL is reverse cholesterol transport, whereby HDL removes cholesterol from plaque macrophage foam cells and delivers it to the liver for processing and excretion into bile. Indeed, in several studies, HDL has shown inverse associations between HDL cholesterol efflux capacity and ASCVD in humans. Inflammation plays a key role in the pathogenesis of atherosclerosis and vulnerable plaque formation, and a fundamental function of HDL is suppression of inflammatory signaling in macrophages and other cells. Oxidation is also a critical process to ASCVD in promoting atherogenic oxidative modifications of LDL (low-density lipoprotein) and cellular inflammation. HDL and its proteins including apoAI (apolipoprotein AI) and PON1 (paraoxonase 1) prevent cellular oxidative stress and LDL modifications. Importantly, HDL in humans with ASCVD is oxidatively modified rendering HDL dysfunctional and proinflammatory. Modification of HDL with reactive carbonyl species, such as malondialdehyde and isolevuglandins, dramatically impairs the antiatherogenic functions of HDL. Importantly, treatment of murine models of atherosclerosis with scavengers of reactive dicarbonyls improves HDL function and reduces systemic inflammation, atherosclerosis development, and features of plaque instability. Here, we discuss the HDL antiatherogenic functions in relation to oxidative modifications and the potential of reactive dicarbonyl scavengers as a therapeutic approach for ASCVD.